The invention concerns a process for the preparation of N.sup..tau. -substituted histidine derivatives, N.sup..tau. -substituted histidine derivatives, and the use thereof for the preparation of peptide derivatives, especially highly active hormone derivatives and enzyme derivatives.
Relatively early, proof was obtained of the existence of the two isomeric amino acids 1-methylhistidine of Formula 6 below and 3-methylhistidine of Formula 7 below, according to IUPAC nomenclature N.sup..pi. -(pros)- and N.sup..tau. -(tele)-methylhistidine: ##STR3##
N.sup..pi. -Methylhistidine was recognized as early as 1938 as a component of anserine, a dipeptide of the structure .beta.-alanyl-L-N.sup..pi. -methylhistidine, which was proven to exist in meat extracts.
The free amino acid N.sup..pi. -methylhistidine was isolated--just as the N.sup..tau. -methyl compound--for the first time from urine. The compound isomeric with respect to anserine, namely .beta.-Ala-L-N.sup..tau. -methyl-His, could be isolated from whale meat.
The amino acid N.sup..tau. -methylhistidine is a component of the myofibrillar proteins actin and myosin which contain practically all of the 3-methylhistidine formed in the body. Methylation takes place only after incorporation of histidine into the respective peptide chain.
Various reports can be found in the literature regarding experiments for the production of N.sup..tau. - and N.sup..pi. -alkylated histidine derivatives. Attempts have been made to introduce the correspondingly substituted nitrogen during the course of a total synthesis of the molecule. This has been tried repeatedly for the N.sup..tau. -histidines [H. H. Tallan, W. H. Stein, and S. Moore, J. Biol. Chem. 206:825 (1954); H. Rinderknecht, T. Rebane, and V. Ma, J. Org. Chem. 293: 1968 (1964); P. K. Martin, H. R. Matthews, H. Rapoport, and G. Thyagarajan, J. Org. Chem. 33:3758 (1968)]. However, the efforts failed due to a non-stereospecific course of the reactions and/or due to lack of a suitable separating method for the thus-obtained racemic mixtures.
Furthermore, attempts have been made to obtain the two isomeric alkyl compounds by direct alkylation of histidine and suitable derivatives. Using the customary alkylation processes, inseparable mixtures of the two isomers were produced in low yields.